High Phe Concentrations Research Articles

Muscle and Bone Health in Young Chilean Adults with Phenylketonuria and Different Degrees of Compliance with the Phenylalanine Restricted Diet.

Three groups were considered-PKU-1: 10 patients who used a protein substitute (PS) without phenylalanine (Phe); PKU-2: 14 patients who used the PS without Phe until eighteen years old and then practiced mostly a vegan diet; and 24 matched healthy controls. A 24 h recall survey, blood parameters, body composition and bone mineral density through DEXA, rectus femoris thickness by ultrasound, hand grip strength, submaximal exercise test, and walking speed were assessed. PKU-1 patients had lower hand grip strength than their matched controls, but no other differences. Compared to controls, the PKU-2 group had lower fat-free mass (p = 0.01), less spine and femoral bone mineral density (p = 0.04 and p < 0.01, respectively), and peak workload on the incremental test (p = 0.03). When comparing PKU groups, blood Phe levels were significantly lower in the PKU-1 group (p = 0.02). Among PKU patients, abandoning the dietary treatment and maintaining high blood Phe concentrations could be deleterious for muscles and bones. However, we cannot discard other causes of bone and muscle damage in these patients.

Increased cytokine levels induced by high phenylalanine concentrations in late diagnosis PKU patients compared to early diagnosis: Anti-inflammatory effect of L-carnitine.

Phenylketonuria (PKU) was the first genetic disease to have an effective therapy, which consists of phenylalanine intake restriction. However, there are patients who do not adhere to treatment and/or are not submitted to neonatal screening. PKU patients present L-carnitine (L-car) deficiency, compound that has demonstrated an antioxidant and anti-inflammatory role in metabolic diseases. This study evaluated the effect caused by exposure time to high Phe levels in PKU patients at early and late diagnosis, through pro- and anti-inflammatory cytokines, as well as the L-car effect in patients under treatment. It was observed that there was a decrease in phenylalanine levels in treated patients compared to patients at diagnosis, and an increase in L-car levels in the patients under treatment. Inverse correlation between Phe versus L-car and nitrate plus nitrite versus L-car in PKU patients was also showed. We found increased proinflammatory cytokines levels: interleukin (IL)-1β, interferons (IFN)-gamma, IL-2, tumor necrosis factor (TNF)-alpha, IL-8 and IL-6 in the patients at late diagnosis compared to controls, and IL-8 in the patients at early diagnosis and treatment compared to controls. Increased IL-2, TNF-alpha, IL-6 levels in the patients at late diagnosis compared to early diagnosis were shown, and reduced IL-6 levels in the treated patients compared to patients at late diagnosis. Moreover, it verified a negative correlation between IFN-gamma and L-car in treated patients. Otherwise, it was observed that there were increased IL-4 levels in the patients at late diagnosis compared to early diagnosis, and reduction in treated patients compared to late diagnosed patients. In urine, there was an increase in 8-isoprostane levels in the patients at diagnosis compared to controls and a decrease in oxidized guanine species in the treated patients compared to the diagnosed patients. Our results demonstrate for the first time in literature that time exposure to high Phe concentrations generates a proinflammatory status, especially in PKU patients with late diagnosis. A pro-oxidant status was verified in not treated PKU patients. Our results demonstrate the importance of early diagnosis and prompt start of treatment, in addition to the importance of L-car supplementation, which can improve cellular defense against inflammation and oxidative damage in PKU patients.

Clinical, genetic, and experimental research of hyperphenylalaninemia.

Hyperphenylalaninemia (HPA) is the most common amino acid metabolism defect in humans. It is an autosomal-recessive disorder of the phenylalanine (Phe) metabolism, in which high Phe concentrations and low tyrosine (Tyr) concentrations in the blood cause phenylketonuria (PKU), brain dysfunction, light pigmentation and musty odor. Newborn screening data of HPA have revealed that the prevalence varies worldwide, with an average of 1:10,000. Most cases of HPA result from phenylalanine hydroxylase (PAH) deficiency, while a small number of HPA are caused by defects in the tetrahydrobiopterin (BH4) metabolism and DnaJ heat shock protein family (Hsp40) member C12 (DNAJC12) deficiency. Currently, the molecular pathophysiology of the neuropathology associated with HPA remains incompletely understood. Dietary restriction of Phe has been highly successful, although outcomes are still suboptimal and patients find it difficult to adhere to the treatment. Pharmacological treatments, such as BH4 and phenylalanine ammonia lyase, are available. Gene therapy for HPA is still in development.

High phenylalanine concentrations induce demyelination and microglial activation in mouse cerebellar organotypic slices

Phenylketonuria (PKU) is an inborn error of metabolism. Mutations in the enzyme phenylalanine hydroxylase (PAH)-encoding gene lead to a decreased metabolism of the amino acid phenylalanine (Phe). The deficiency in PAH increases Phe levels in blood and brain. Accumulation of Phe can lead to delayed development, psychiatric problems and cognitive impairment. White matter (WM) damage is a neuropathological hallmark of PKU and can be seen even in early detected and treated PKU patients. The mechanisms linking high Phe concentrations to WM abnormalities remain unclear. We tested the effects of high Phe concentrations on myelin in three in vitro models of increasing complexity: two simple cell culture models and one model that preserves local brain tissue architecture, a cerebellar organotypic slice culture prepared from postnatal day (P) 8 CD-1 mice. Various Phe concentrations (0.1–10 mM) and durations of exposure were tested. We found no toxic effect of high Phe in the cell culture models. On the contrary, the treatment promoted the maturation of oligodendrocytes, particularly at the highest, non-physiological Phe concentrations. Exposure of cerebellar organotypic slices to 2.4 mM Phe for 21 days in vitro (DIV), but not 7 or 10 DIV, resulted in a significant decrease in myelin basic protein (MBP), calbindin-stained neurites, and neurites co-stained with MBP. Following exposure to a toxic concentration of Phe, a switch to the control medium for 7 days did not lead to remyelination, while very active remyelination was seen in slices following demyelination with lysolecithin. An enhanced number of microglia, displaying an activated type morphology, was seen after exposure of the slices to 2.4 mM Phe for 10 or 21 DIV. The results suggest that prolonged exposure to high Phe concentrations can induce microglial activation preceding significant disruption of myelin.

Phenanthrene induces autism-like behavior by promoting oxidative stress and mTOR pathway activation

Autism is thought to be associated with both environmental and genetic factors. Phenanthrene (Phe) makes up a relatively high proportion of the low-ring polycyclic aromatic hydrocarbons. However, the association between exposure to Phe and Autism remain unclear. In this study, the effect and mechanisms of phenanthrene exposure on autistic behavior were investigated. Three-week-old male Kunming mice were exposed to doses of 5, 50, or 500 μg/kg/d Phe for 22 days. Exposure to phenanthrene induced a marked decrease in the activity of the mice in the central area in the open field test, and caused a significant decrease in communication with unfamiliar mice in the three-chambered social test. The hippocampus of the mice exposed to high concentrations of Phe showed pathological changes. Exposure to phenanthrene induced an increase in the levels of ROS and a decrease in levels of glutathione, and caused a significant decrease in the expression of Shank3 and Beclin1. This also led to an increase in the phosphorylation levels of Akt and mTOR. However, administering Rapamycin or vitamin E, inhibited the oxidative stress and activation of the mTOR pathway induced by Phe exposure, effectively alleviating the above-mentioned autistic-like anxious social behaviors. These results indicate that exposure to phenanthrene will lead to autism-like behavior. The underlying mechanism involves oxidative stress and the mTOR pathway.

Both α1B- and α1A-adrenoceptor subtypes are involved in contractions of rat spleen.

The spleen is a reservoir for circulating blood cells, and can contract to expel them. We have investigated the adrenoceptors involved in isometric contractions of rat spleen produced by noradrenaline (NA) and the α1-adrenoceptor agonist phenylephrine (Phe). Contractions to NA were antagonized by both the α1-adrenoceptor antagonist prazosin (10-8M) and the α2-adrenoceptor antagonist yohimbine (10-6M), and the combination produced further shifts in NA potency. Contractions to Phe were antagonized by prazosin (10-8M) which caused a marked parallel shift in the concentration-response curve. High non-selective concentrations of the α1D-adrenoceptor antagonist BMY7378 (10-6M), the α1A-adrenoceptor antagonist RS100329 ((3×10-8M), and the putative α1B-adrenoceptor antagonist cyclazosin (10-8M) also produced parallel shifts in the Phe concentration-response curve. BMY7378 at the selective concentration of 3×10-8M had no effect on responses to Phe, but RS100329 in the selective concentration of 3×10-9M produced a marked shift in the effects of high concentrations of Phe. Hence, antagonists in concentrations that block both α1A- and α1B-adrenoceptors produce approximately parallel shifts in Phe potency. Contractions of rat spleen to adrenergic agonists involve α2- and α1B-adrenoceptors, with a lesser role for α1A-adrenoceptors. This confirms the suggestion that smooth muscle contractions commonly involve multiple subtypes.

Biomimetic synthesis of calcium carbonate under phenylalanine: Control of polymorph and morphology.

In biomineralization, organisms have the abilities to produce biominerals with superior properties. One of the most attractive features of biominerals is the presence of the proteins consisting of different contents of amino acids in crystals. In the present work, L-phenylalanine (Phe) was used as an additive for the controllable crystallization of calcium carbonate (CaCO3). The obtained CaCO3 crystals were characterized by field emission scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), elemental analysis and high-resolution transmission electron microscopy (HRTEM). The experimental results suggest that single calcite crystals are formed at low Phe concentrations. High concentrations of Phe inhibit the nucleation and growth of calcite, and promote the formation of vaterite crystals with solid or hollow structures. The morphology and crystal form of CaCO3 are also significantly affected by the flow rate of CO2. After that, a possible mechanism (competition mechanism) action of Phe in the formation of CaCO3 is proposed. Finally, the effects of temperature on the formation of vaterite were determined to explore the growth mechanism of hexagonal vaterite. The work of controlling the preparation of CaCO3 crystals in the presence of Phe will help us to imitate and learn nature, and bring new insights into understanding bionics. Meanwhile, it provides a new method for the synthesis of CaCO3 biomaterials with different crystal forms and morphologies.

Single and joint oxidative stress of cadmium and phenanthrene on the Bivalve Anadara subcrenata

Single and joint oxidative stress of cadmium (Cd) and phenanthrene (Phe) on Anadara subcrenata were investigated under laboratory conditions with biomarkers such as reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and total antioxidant capacity (TAOC). The results indicated that the ROS level in Anadara subcrenata exposed to Cd and Phe significantly (P < 0.05) increased during the early exposure stage, and the TAOC level and SOD activity were induced as the response of the antioxidant defense system, and this followed a damage, recovery or acclimation event. The MDA content was negatively correlated with SOD activity. As the time went on, the ROS level decreased gradually and was close to that in the control after 9 days; the TAOC level decreased accordingly, but the recovery rate of the SOD activity was slower than that of the TAOC level. High concentrations of Cd or Phe had a stronger oxidative stress effect on Anadara subcrenata. Phe had a stronger effect on the SOD activity of Anadara subcrenata. The joint effects of Cd and Phe on the levels of ROS and TAOC, SOD activity and MDA content in Anadara subcrenata are dependent on their concentration combination, which were called the double-dose dependent effects and time-dependent effects, respectively. The binary mixture treatments of 477.33 μg/L Cd and 48.08 μg/L Phe had the highest oxidative stress on Anadara subcrenata.

Simulations of the regulatory ACT domain of human phenylalanine hydroxylase (PAH) unveil its mechanism of phenylalanine binding

Phenylalanine hydroxylase (PAH) regulates phenylalanine (Phe) levels in mammals to prevent neurotoxicity resulting from high Phe concentrations as observed in genetic disorders leading to hyperphenylalaninemia and phenylketonuria. PAH senses elevated Phe concentrations by transient allosteric Phe binding to a protein-protein interface between ACT domains of different subunits in a PAH tetramer. This interface is present in an activated PAH (A-PAH) tetramer and absent in a resting-state PAH (RS-PAH) tetramer. To investigate this allosteric sensing mechanism, here we used the GROMACS molecular dynamics simulation suite on the Folding@home computing platform to perform extensive molecular simulations and Markov state model (MSM) analysis of Phe binding to ACT domain dimers. These simulations strongly implicated a conformational selection mechanism for Phe association with ACT domain dimers and revealed protein motions that act as a gating mechanism for Phe binding. The MSMs also illuminate a highly mobile hairpin loop, consistent with experimental findings also presented here that the PAH variant L72W does not shift the PAH structural equilibrium toward the activated state. Finally, simulations of ACT domain monomers are presented, in which spontaneous transitions between resting-state and activated conformations are observed, also consistent with a mechanism of conformational selection. These mechanistic details provide detailed insight into the regulation of PAH activation and provide testable hypotheses for the development of new allosteric effectors to correct structural and functional defects in PAH.

Investigation of Fibril Forming Mechanisms of l-Phenylalanine and l-Tyrosine: Microscopic Insight toward Phenylketonuria and Tyrosinemia Type II.

Phenylketonuria and tyrosinemia type II, the two metabolic disorders, are originated due to the complications in metabolism of phenylalanine (Phe) and tyrosine (Tyr), respectively. Several neurological injuries, involving microcephaly, mental retardation, epilepsy, motor disease, and skin problems etc., are the symptoms of these two diseases. It has been reported that toxic amyloid fibrils are formed at high concentrations of Phe and Tyr. Our study indicates that the fibril forming mechanisms of Phe and Tyr are completely different. In the case of Phe, -NH3+ and -COO- groups of neighboring molecules interact via hydrogen bonding and polar interactions. On the other hand, there is no role of - NH3+ group in the fibril forming mechanism of Tyr. In Tyr fibril, the two hydrogen bonding partners are -OH and -COO- groups. In addition, we have also investigated the effect of three lanthanide cations on the fibrillar assemblies of Phe. It has been observed that the efficiencies of three lanthanides to inhibit the fibrillar assemblies of Phe follow the order Tb3+< Sm3+< Eu3+.

Effects of penicillamine, hypotaurine, and epinephrine on motility, hyperactivity, acrosome reaction of fresh ram sperm

Objective: To determine the effects of different concentrations of penicillamine, hypotaurine, and epinephrine (PHE) as well as incubation time on motility, hyperactivity and acrosome reaction (AR) of ram sperm in vitro. Methods: Freshly ejaculated spermatozoa from three ram were collected, pooled and subjected to swim up technique in modified sperm Tyrode's albumin lactate pyruvate medium supplemented with different concentrations of PHE (10, 20, 30, 40, 50, 75 and 100 mM/mL). Then best concentrations were compared and examined for motility, hyperactivity and AR. Results: A high concentrations of PHE (30, 40, 50, 75 and 100mM/mL) showed a significant increase in motility when compared to control immediately after dilution and exist for the first and second hour of incubation period. However, when longer incubation time were used, a significant (P

20 EFFECT OF PENICILLAMINE, HYPOTAURINE, AND EPINEPHRINE TREATMENT ON MOTILITY, HYPERACTIVITY AND ACROSOME REACTION OF RAM SPERMATOZOA

The aim of this study was to determine the effects of in vitro treatment of freshly ejaculated ram spermatozoa with different concentrations of penicillamine, hypotaurine, and epinephrine (PHE) at different incubation times on motility, hyperactivity (HA) and acrosome reaction (AR). Freshly ejaculated spermatozoa collected from three rams were pooled and then subjected to swim up technique in modified sperm Tyrode’s albumin lactate pyruvate (S-TALP) medium supplemented with different concentrations of PHE (0, 10, 20, 30, 40, 50, 75, and 100 mM). Following incubation (0, 1, 2, 3 and 4 h), sperm motility and hyperactivity were examined under the phase contrast microscope and acrosome reaction was detected by staining of the spermatozoa with silver nitrate. Results showed that treatment of spermatozoa with high concentrations of PHE (30, 40, 50, 75, and 100 mM) significantly increased the motility when compared with the control immediately after dilution (82.0, 82.0, 81.0, 82.0, 82.0 v.76.0%, respectively).This increase existed for the first and second hours of incubation. However, when the incubation time was increased for more than 2 h total motility significantly decreased (P &lt; 0.05, ANOVA) as compared with the control. The same trend was observed in hyperactive motility. Treatment of spermatozoa with 50 and 75 mM of PHE for 1 h significantly increased the percentage of sperm with incomplete AR (20.0 and 27.0% respectively). At 4 h incubation, (49.0%) of spermatozoa treated with 75 mM PHE had undergone complete AR. Furthermore, the maximum value of total acrosome reaction (73.0%) was achieved at 4 h post incubation after addition of 75 mM PHE to ram sperm. In conclusion, under our experimental conditions, 75 mM PHE for 4 h was considered the best concentration of PHE for treatment of ejaculated ram spermatozoa for in vitro induction of acrosome reaction.

Evaluation of Tetrahydrobiopterin Therapy with Large Neutral Amino Acid Supplementation in Phenylketonuria: Effects on Potential Peripheral Biomarkers, Melatonin and Dopamine, for Brain Monoamine Neurotransmitters.

BackgroundPhenylketonuria (PKU) is due to a defective hepatic enzyme, phenylalanine (Phe) hydroxylase. Transport of the precursor amino acids from blood into the brain for serotonin and dopamine synthesis is reported to be inhibited by high blood Phe concentrations. Deficiencies of serotonin and dopamine are involved in neurocognitive dysfunction in PKU.Objective(1) To evaluate the effects of sapropterin (BH4) and concurrent use of large neutral amino acids (LNAA) on the peripheral biomarkers, melatonin and dopamine with the hypothesis they reflect brain serotonin and dopamine metabolism. (2) To evaluate synergistic effects with BH4 and LNAA. (3) To determine the effects of blood Phe concentrations on the peripheral biomarkers concentrations.MethodsNine adults with PKU completed our study consisting of four 4-week phases: (1) LNAA supplementation, (2) Washout, (3) BH4 therapy, and (4) LNAA with BH4 therapy. An overnight protocol measured plasma amino acids, serum melatonin, and 6-sulfatoxymelatonin and dopamine in first void urine after each phase.Results(1) Three out of nine subjects responded to BH4. A significant increase of serum melatonin levels was observed in BH4 responders with decreased blood Phe concentration. No significant change in melatonin, dopamine or Phe levels was observed with BH4 in the subjects as a whole. (2) Synergistic effects with BH4 and LNAA were observed in serum melatonin in BH4 responders. (3) The relationship between serum melatonin and Phe showed a significant negative slope (p = 0.0005) with a trend toward differing slopes among individual subjects (p = 0.066). There was also a negative association overall between blood Phe and urine 6-sulfatoxymelatonin and dopamine (P = 0.040 and 0.047).ConclusionBlood Phe concentrations affected peripheral monoamine neurotransmitter biomarker concentrations differently in each individual with PKU. Melatonin levels increased with BH4 therapy only when blood Phe decreased. Monitoring peripheral neurotransmitter metabolites may assist in optimizing individualized treatment in PKU.

Meta-analysis of the response of growing pigs to the isoleucine concentration in the diet

The efficiency of nitrogen utilization will be highest when the amino acid (AA) supply approaches the requirement of the animal. With the availability of different crystalline AA, it is theoretically possible to formulate low-protein diets for growing pigs in which seven AA are co-limiting for performance. In such a diet, the concentration of Lys, Met, Met + Cys, Thr, Trp and Val and a seventh AA would exactly match the requirement. To determine the extent to which low-protein diets can be used, it is important to have reliable information about the requirements for these AA. Isoleucine is often considered the seventh-limiting AA in diets for growing pigs; however, information about the Ile requirement is limited and sometimes conflicting. The purpose of this study was to carry out a meta-analysis of the available literature information to determine the Ile requirement in growing pigs. A total of 46 Ile dose–response experiments were identified that used at least four concentrations of Ile in the diet. Because of differences in experimental design, both the Ile concentration and the response criteria were standardized. In 13 dose–response experiments, there was no indication of a response to an increasing Ile concentration. For the other 33 experiments, a response to the increasing Ile concentration was observed and the Ile requirement estimates ranged from 53% to 114% of that of the National Research Council (1998). An Ile concentration below the requirement resulted in important reductions in both feed intake and growth. A 10% reduction in the Ile concentration (below the requirement) resulted in a 15% reduction in feed intake and a 21% reduction in daily gain. The use of blood products in the diet was the main factor determining whether a response to the Ile concentration was observed or not. Blood meal and blood cells are protein sources with a very low Ile concentration, but with high or very high concentrations of Leu, Val, Phe and His. Some of these AA compete with Ile for catabolic pathways or transport across the blood–brain barrier, thereby potentially increasing the requirement for Ile. In diets without blood products, the Ile requirement appears to be lower than the currently recommended requirement. On the basis of the outcome of this study, we recommend a Ile : Lys requirement ratio of at least 50% on a standardized ileal digestible basis.

Effect Factors of Biodegradation on Phenanthrene by &lt;i&gt;Pseudomonas putida&lt;/i&gt;

Abstract. This study discussed the effect factors of biodegradation on phenanthrene by P.putida. The outcomes showed that the optimal temperature conditions was 35°C, and the optimal pH was pH7.5, and that under the shaking condition increases the availability of phe. The effect of glucose increase in the concentration of glucose showed repressive effect. Moreover, the presence of salicylate increased the phenanthrene degradation to some extent. Phenanthrene degradation in presence of succinic acid did not differ significantly, this implies that the presence of other carbon sources does not completely inhibited. Therefore, phenanthrene may be co-utilized by p. putida along with other substrates. And that the addition of non-ionic surfactants bring about further phe biodegradation, the biodegradability of phe is greatly improved in presence of surfactants at proper concentrations. The phenanthrene was degraded higher efficiently at higher phe concentrations under the presence of fluorene, phe and fluorene present an obviously co-metabolism.

Born at 27 weeks of Gestation with Classical PKU: Challenges of Dietetic Management in a very Preterm Infant

Few cases of premature infants with classical phenylketonuria (PKU) have been reported. Treatment of these patients is challenging due to the lack of a phenylalanine (Phe)-free amino acid (AA) solution for parenteral nutrition. A boy born at 27 weeks of gestation with a weight of 1000 g was diagnosed with classical PKU on day 7 because of highly elevated Phe level at newborn screening (2800 µmol/L). Phe intake was suspended for 5 days and during this time intravenous glucose and lipids as well as small amounts of Phe-free formula through nasogastric tube were given. Because of insufficient weight gain attributable to deficiency of essential AA, a Phe-reduced, BCAA-enriched parenteral nutrition was added to satisfy AA requirements without overloading in Phe. Under this regimen, the boy started to gain weight, Phe plasma levels progressively reduced and normalized on day 19. At the age of 40 months, the patient shows normal growth parameters (height 25th percentile, weight 25–50th percentile, head circumference 50th percentile) with a normal result for formally tested psychomotor development (WPPSI-III). The good outcome of the patient in spite of over 2 weeks of extremely high Phe concentrations suggests that the premature brain may still have enough plasticity to recover. Lacking a Phe-free intravenous AA solution, successful management of premature infants with PKU depends on the child's tolerance of enteral nutrition. Although the coincidence of PKU and prematurity is rare, there is strong need for the development of an appropriate Phe-free amino acid solution for parenteral nutrition especially in case of gastro-intestinal complications of prematurity.

Oligodendrocyte development and myelinogenesis are not impaired by high concentrations of phenylalanine or its metabolites

Phenylketonuria (PKU) is a metabolic genetic disease characterized by deficient phenylalanine hydroxylase (PAH) enzymatic activity. Brain hypomyelination has been reported in untreated patients, but its mechanism remains unclear. We therefore investigated the influence of phenylalanine (Phe), phenylpyruvate (PP), and phenylacetate (PA) on oligodendrocytes. We first showed in a mouse model of PKU that the number of oligodendrocytes is not different in corpus callosum sections from adult mutants or from control brains. Then, using enriched oligodendroglial cultures, we detected no cytotoxic effect of high concentrations of Phe, PP, or PA. Finally, we analyzed the impact of Phe, PP, and PA on the myelination process in myelinating cocultures using both an in vitro index of myelination, based on activation of the myelin basic protein (MBP) promoter, and the direct quantification of myelin sheaths by both optical measurement and a bioinformatics method. None of these parameters was affected by the increased levels of Phe or its derivatives. Taken together, our data demonstrate that high levels of Phe, such as in PKU, are unlikely to directly induce brain hypomyelination, suggesting involvement of alternative mechanisms in this myelination defect.

Undiagnosed maternal phenylketonuria: own clinical experience and literature review

Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism resulting from deficiency of phenylalanine hydroxylase (PAH). Most forms of PKU are caused by mutations in the PAH gene. Untreated PKU is associated with an abnormal phenotype, which includes growth failure, seizures, global developmental delay and severe intellectual impairment. The maternal PKU (MPKU) syndrome is caused by high blood Phe concentrations during pregnancy and presents with serious foetal anomalies, especially microcephaly, congenital heart disease and mental retardation. However, since the introduction of newborn screening programs and with early dietary intervention, children born with PKU can now expect to lead relatively normal lives. We present the case of a 33-year-old woman who had been diagnosed as having PKU only after a pregnancy with MPKU embryopathy, to emphasize that undiagnosed maternal phenylketonuria still exists. On that ground, we reviewed updated literature on the pathogenesis of this syndrome, possibility of prophylaxis and treatment.

Increased spontaneous osteoclastogenesis from peripheral blood mononuclear cells in phenylketonuria

Phenylketonuria (PKU) is commonly complicated by a progressive bone impairment of uncertain aetiology. The therapeutic phenylalanine (Phe)-restricted diet and the possible noxious effects of high plasma Phe concentrations on bone have previously been suggested as possible determinant factors. Since osteoclasts are involved in bone reabsorption, they could play a role in determining bone damage in PKU. The reported increased excretion of bone resorption markers in PKU patients is consistent with this hypothesis. Although different diseases characterized by bone loss have been related to increased spontaneous osteoclastogenesis from peripheral blood mononuclear cells (PBMCs), to date there is no evidence of increased osteoclast formation in PKU. In this study, we compared the spontaneous osteoclastogenesis from PBMCs in 20 patients affected by PKU with that observed in age- and sex-matched healthy subjects. Phenylketonuric patients showed the number of osteoclasts to be almost double that observed in controls (159.9 ± 79.5 and 87.8 ± 44.7, respectively; p = 0.001). Moreover, a strict direct correlation between the spontaneous osteoclastogenesis in PKU patients and the mean blood Phe concentrations in the preceding year was observed (r = 0.576; p = 0.010). An imbalance between bone formation and bone resorption might explain, at least in part, the pathogenesis of bone loss in this disease. These findings could provide new insights into the biological mechanisms underlying bone damage in PKU.

Characterization of white matter alterations in phenylketonuria by magnetic resonance relaxometry and diffusion tensor imaging

A multimodal MR study including relaxometry, diffusion tensor imaging (DTI), and MR spectroscopy was performed on patients with classical phenylketonuria (PKU) and matched controls, to improve our understanding of white matter (WM) lesions. Relaxometry yields information on myelin loss or malformation and may substantiate results from DTI attributed to myelin changes. Relaxometry was used to determine four brain compartments in normal-appearing brain tissue (NABT) and in lesions: water in myelin bilayers (myelin water, MW), water in gray matter (GM), water in WM, and water with long relaxation times (cerebrospinal fluid [CSF]-like signals). DTI yielded apparent diffusion coefficients (ADCs) and fractional anisotropies. MW and WM content were reduced in NABT and in lesions of PKU patients, while CSF-like signals were significantly increased. ADC values were reduced in PKU lesions, but also in the corpus callosum. Diffusion anisotropy was reduced in lesions because of a stronger decrease in the longitudinal than in the transverse diffusion. WM content and CSF-like components in lesions correlated with anisotropy and ADC. ADC values in lesions and in the corpus callosum correlated negatively with blood and brain phenylalanine (Phe) concentrations. Intramyelinic edema combined with vacuolization is a likely cause of the WM alterations. Correlations between diffusivity and Phe concentrations confirm vulnerability of WM to high Phe concentrations.